Growth factors and their receptors play critical roles in the regulation of cell growth and metabolism in both normal tissues, and malignancies. The hypothesis we are testing is that transmembrane protein tyrosine phosphatases (PTPases) exert negative regulatory control on critical tyrosine kinase signaling pathways. The role of PTPases in two pathologic states are under active investigation: diabetes and metastatic breast cancer. Cell model systems and transgenic knockout mice are the focus of investigations into candidate PTPases potentially involved in these disease states.

       Using transfection techniques, we have demonstrated that receptor dependent signaling decreases by as much as 70% in the presence of over-expressed PTPases. Using a more direct approach, we have suppressed the expression of the PTPase, LAR, by 60% with antisense expression vectors in a hepatoma cell line with a resulting amplification of insulin receptor signaling by 300-400%. This clearly implicates LAR as an important regulator of insulin receptor signaling in liver and raises the question whether LAR is involved in insulin resistance and diabetes.

       In summary, our investigations into the role of transmembrane PTPases have provided strong support for our hypothesis that these enzymes play a critical role in regulating tyrosine kinase receptor signaling. Continuing work will focus on identifying the PTPases involved in specific tyrosine kinase receptor signaling pathways. Characterizing PTPase-receptor interactions will further our understanding of the normal regulatory mechanisms in cell growth, differentiation, and metabolic regulation as well as aberrant cell processes such as cancer metastatic and diabetes.

Recent Publications

Klover PJ, Clementi AH, Mooney RA. 2005. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology. Aug;146(8):3417-27

LeVea CM, Reeder JE, and Mooney RA. 2004 EGF-dependent cell cycle progression is controlled by density-dependent regulation of Akt activation. Exp Cell Res. Jul 1;297(1):272-284.

Klover PJ and Mooney RA. 2004. Hepatocytes: critical for glucose homeostasis. Int J Biochem Cell Biol. May;36(5):753-758. Review.

Baliff JP and Mooney RA. 2003. New developments in prenatal screening for Down syndrome. Am J Clin Pathol. Dec;120 Suppl:S14-24. Review

Arnold GL, Hyman SL, Mooney RA, and Kirby RS. 2003. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord. Aug;33(4):449-454.

Polliotti BM, Fry AG, Saller DN, Mooney RA, Cox C, and Miller RK. 2003. Second-trimester maternal serum placental growth factor and vascular endothelial growth factor for predicting severe, early-onset preeclampsia. Obstet Gynecol. Jun;101(6):1266-74.

Mooney RA and LeVea CM. 2003. The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. Curr Top Med Chem. 3(7):809-819. Review.

Senn JJ, Klover PJ, Nowak IA, Zimmers TA, Koniaris LG, Furlanetto RW, Mooney RA. 2003. Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J Biol Chem. Apr 18;278(16):13740-6.